OP0204 CIRCULATING CD4+CXCR5+PD-1HI FOLLICULAR HELPER T CELLS ARE ELEVATED IN PATIENTS WITH RHEUMATOID ARTHRITIS AND PREDICT TREATMENT RESPONSE TO ABATACEPT OR TNF BLOCKERS
Authors: I. Monjo, B. Nieto-Carvalhal, M. D. C. Uyaguari, A. Villalba, L. Nuño, D. Peiteado, E. Fernandez, S. Garcia-Carazo, A. Balsa, M. E. Miranda-Carus
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> CD4+CXCR5+PD-1<sup>hi</sup> follicular helper (Tfh) T cells typically dwell in the germinal centers (GCs) of lymphoid organs, provide help to autoantibody secreting B cells and play an important role in the pathogenesis of Rheumatoid Arthritis (RA). Circulating counterparts of Tfh (cTfh) cells have been described in human peripheral blood, their frequencies seem to correlate with the pool of prototypical GC Tfh cells, and are expanded in patients with autoimmune conditions including RA. Abatacept (ABT), by interfering with costimulation, can restrain the generation of Tfh cells. The pathogenic implication of Tfh cells may be more prominent in RA patients with higher cTfh cell frequencies and these subjects could be more likely to respond to therapeutic costimulation blockade with ABT. <h3>Objectives</h3> To examine a). The effect of treatment escalation using TNF blockers (TNFb) or ABT, on the frequency of cTfh cells in RA, and b). The relation of the baseline cTfh cell frequency with the clinical response. <h3>Methods</h3> Peripheral blood was drawn from seropositive RA patients with an incomplete response to csDMARDS (n=41) who initiated biological therapy, according to routine clinical practice, with TNFb (n= 19) (10 Etanercept, 3 Adalimumab, 3 Certolizumab, 2 Golimumab, 1 Infliximab) or ABT (n= 22). cTfh cell frequencies were determined by flow cytometry of freshly isolated PBMCs at the basal visit and 12 months (12M) after starting treatment escalation. For each patient, an age and gender-matched healthy control (HC) was also studied at both time points (n=41). <h3>Results</h3> a). Effect of treatment escalation on the cTfh cell frequency. As compared with HC, RA patients receiving csDMARDs demonstrated an increased frequency of cTfh and also of activated ICOS+ cTfh cells (a-cTfh), and this was observed in both treatment escalation groups. A significant improvement of disease activity (ΔDAS28 &gt;2.0) was apparent in all of the patients at 12M. Nevertheless, the cTfh cell frequency did not vary in patients receiving TNFb; conversely, in subjects receiving ABT it significanly decreased to HC levels. At the same time, the frequency of a-cTfh cells was significantly reduced in both groups; however, in the TNFb group it remained above HC whereas in the ABT group it reached magnitudes comparable to HC. b). Relation of the baseline cTfh cell frequency with the clinical response. In the ABT group, the baseline frequencies of cTfh and a-cTfh had been higher for patients who went on to achieve remission at 12M (12Mr), as compared with those who remained active (12Ma) [Tfh logistic regression OR for remission 25.3, 95% CI (12.2-39.8); ROC AUC 0.94(0.83-1), p&lt;0.0005]; as stated above, the 12M frequencies were no longer elevated; in addition there were no differences between the 12Ma and 12Mr subjects. Conversely, in the TNFb group, the baseline frequencies of cTfh and a-cTfh had been lower for 12Mr as compared with 12Ma patients [Tfh OR for not achieving remission 8.5 (4.3-15.5); ROC AUC 0.77(0.54-0.99), p&lt;0.05]; furthermore, the 12M frequencies showed the same pattern: they had not significantly changed, persisted elevated above HC and remained lower in 12Mr as compared with 12Ma patients. The baseline cTfh cutoff frequency for achieving remission in the ABT group was &gt;0.35% (sensitivity 92.7%, specificity 90%). The baseline cTfh cutoff frequency for not achieving remission in the TNFb group was &gt;0.44% (sensitivity 67.7%, specificity 90%). <h3>Conclusion</h3> ABT but not TNFb, is able to curtail cTfh cell numbers in RA, suggesting that costimulation blockade can restrain germinal center overactivity. Higher baseline cTfh cell frequencies predict a good response to ABT and at the same time, a poor response to TNFb. Therefore, immunophenotyping of patients with an incomplete response to csDMARDs can facilitate a personalized therapeutic strategy for treatment escalation. <h3>References</h3> [1]Vinuesa CG, Cook MC. Immunity. 2011 [2]Craft J, Nat Rev Rheumatol 2012 [3]Arroyo-Villa I et al., Arthritis Res Ther 2014 [4]Aldridge J, et al. Rheumatology (Oxford) 2022. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Irene Monjo: None declared, Beatriz Nieto-Carvalhal: None declared, Mariela del Carmen Uyaguari: None declared, Alejandro Villalba: None declared, Laura Nuño: None declared, Diana Peiteado: None declared, Elisa Fernandez: None declared, Sara Garcia-Carazo: None declared, Alejandro Balsa Grant/research support from: BMS, Gebro Pharma, Maria-Eugenia Miranda-Carus Grant/research support from: BMS, Gebro Pharma.